2. Academic Validation
  3. Punicalagin as a novel selective aryl hydrocarbon receptor (AhR) modulator upregulates AhR expression through the PDK1/p90RSK/AP-1 pathway to promote the anti-inflammatory response and bactericidal activity of macrophages

Punicalagin as a novel selective aryl hydrocarbon receptor (AhR) modulator upregulates AhR expression through the PDK1/p90RSK/AP-1 pathway to promote the anti-inflammatory response and bactericidal activity of macrophages

  • Cell Commun Signal. 2024 Oct 3;22(1):473. doi: 10.1186/s12964-024-01847-9.
Weihong Dai # 1 2,  Shuangqin Yin # 1,  Fangjie Wang # 1,  Tianyin Kuang # 1,  Hongyan Xiao 1,  Wenyuan Kang 3,  Caihong Yun 2,  Fei Wang 1 2,  Li Luo 1,  Shengxiang Ao 1,  Jing Zhou 1,  Xue Yang 1,  Chao Fan 1,  Wei Li 1,  Dongmei He 1,  He Jin 4,  Wanqi Tang 1,  Lizhu Liu 2,  Rixing Wang 5,  Huaping Liang 6,  Junyu Zhu 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Trauma and Chemical Poisoning, Department of Wound Infection and Drug, Daping Hospital, Army Medical University, Chongqing, 400042, China.
  • 2 Emergency of The Second Affiliated Hospital of Hainan Medical University, Haikou, 571100, China.
  • 3 Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education & Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou, 571158, China.
  • 4 Department of Cardiothoracic Surgery, 926th Hospital of Joint Logistics Support Force of PLA, Kaiyuan, 661600, China.
  • 5 Emergency of The Second Affiliated Hospital of Hainan Medical University, Haikou, 571100, China. wangrx903@163.com.
  • 6 State Key Laboratory of Trauma and Chemical Poisoning, Department of Wound Infection and Drug, Daping Hospital, Army Medical University, Chongqing, 400042, China. 13638356728@163.com.
  • 7 State Key Laboratory of Trauma and Chemical Poisoning, Department of Wound Infection and Drug, Daping Hospital, Army Medical University, Chongqing, 400042, China. zjykent@sina.com.
  • # Contributed equally.
PMID: 39363344 DOI: 10.1186/s12964-024-01847-9
Abstract

Aryl Hydrocarbon Receptor (AhR) plays an important role in inflammation and immunity as a new therapeutic target for infectious disease and sepsis. Punicalagin (PUN) is a Chinese herbal monomer extract of pomegranate peel that has beneficial anti-inflammatory, antioxidant and anti-infective effects. However, whether PUN is a ligand of AhR, its effect on AhR expression, and its signaling pathway remain poorly understood. In this study, we found that PUN was a unique polyphenolic compound that upregulated AhR expression at the transcriptional level, and regulated the AhR nongenomic pathway. AhR expression in lipopolysaccharide-induced macrophages was upregulated by PUN in vitro and in vivo in a time- and dose-dependent manner. Using specific inhibitors and siRNA, induction of AhR by PUN depended on sequential phosphorylation of 90-kDa ribosomal S6 kinase (p90RSK), which was activated by the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and phosphoinositide-dependent protein kinase (PDK)1 pathways. PUN promoted p90RSK-mediated activator protein-1 (AP-1) activation. AhR knockout or inhibitors reversed suppression of interleukin (IL)-6 and IL-1β expression by PUN. PUN decreased Listeria load and increased macrophage survival via AhR upregulation. In conclusion, we identified PUN as a novel selective AhR modulator involved in AhR expression via the MEK/ERK and PDK1 pathways targeting p90RSK/AP-1 in inflammatory macrophages, which inhibited macrophage inflammation and promoted bactericidal activity.

Keywords

Aryl hydrocarbon receptor; Inflammation; Macrophage; Punicalagin; p90RSK.

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